Tetracycline (Oxytetracycline Calcium Complex) Crops 1 2 Identification of Petitioned Substance

3 Chemical Names: CAS Number: 4 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a- 7179-50-2 5 octahydro-3,5,6,10,12,12a-hexahydro-6- 6 methyl-1,11-dioxo-2-naphthacenecarboxamide Other Codes: 7 calcium X1039009-9 (ACX number) 8 006321 (USEPA PC Code) 9 Other Names: 3145 (HSDB number; oxytetracycline) 10 agricultural terramycin 11 calcium oxytetracycline Related Compounds: 12 oxytetracycline calcium complex Oxytetracycline (CAS # 79-57-2) 13 Oxytetracycline 14 Trade Names: hydrochloride (CAS # 2058-46-0) 15 Fireman Tetracycline (CAS # 60-54-8) 16 Mycoject 17 Mycoshield 18 Oxytetracycline calcium technical 19 Tree Tech OTC-CA 20 21 Characterization of Petitioned Substance 22 23 Composition of the Substance: 24 Oxytetracyline calcium complex (C22H22N2O9 Ca) is an agricultural antibiotic pesticide (microbiocide) derived 25 from Streptomyces soil bacteria; it is used to control bacteria and fungi in agricultural crops (EPA 1993a). The 26 chemical structure of the parent compound, oxytetracycline, is shown in Figure 1. 27

28 29 30 Figure 1. Chemical Structure of Oxytetracycline 31 32 This review focuses on “calcium oxytetracycline” (oxytetracycline calcium complex; CAS # 7179-50-2) and 33 pesticides that contain calcium oxytetracycline for use in plant disease control in organic crop production (PAN 34 2006a provides a list of the pesticides). In cases where no information is available specifically for calcium 35 oxytetracycline, related and relevant information for the parent compound oxytetracycline (CAS # 79-57-2) 36 and/or oxytetracycline hydrochloride (CAS # 2058-46-0), a closely related compound, is provided and cited 37 accordingly. The term “oxytetracycline1” is often used broadly to include oxytetracycline itself, calcium 38 oxytetracycline, and oxytetracycline hydrochloride, which all have unique CAS numbers and EPA Pesticide

1 For regulatory purposes, EPA uses the term “oxytetracycline” to refer to pesticides containing calcium oxytetracycline or hydroxytetracycline monohydrochloride (oxytetracycline hydrochloride); there are currently no active pesticide registrations that contain oxytetracycline as the active ingredient (EPA 1993a, 2005a, PAN 2006b). ______January 27, 2006 Technical Evaluation Report Page 1 of 9 Compiled by ICF Consulting for the USDA National Organic Program Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

39 Chemical Codes (EPA 1988, 1993a, HSDB 2003a).2 The term “tetracycline” refers to tetracycline (CAS # 60-54-8) 40 and many tetracycline-derivatives that are used for a wide variety of medical, veterinary, and, to a much lesser 41 extent, agricultural applications (HSDB 2003b). 42 43 Properties of the Substance: 44 Calcium oxytetracycline is an odorless light to dark brown powder that is most commonly produced as a 45 wettable powder (EPA 1993a, Greenbook 2004a). Calcium oxytetracycline is slightly soluble in water 46 (Greenbook 2004a). It is stable under normal use and storage conditions; light and extreme heat should be 47 avoided. At high temperatures, it can decompose and form toxic gases (no information available as to 48 specific gases formed). 49 50 Specific Uses of the Substance: 51 Oxytetracycline calcium complex (calcium oxytetracycline) is currently included on the National List as a 52 synthetic substance allowed in organic crop production “for fire blight control only” (NOP 53 §205.601(i)(11)).3 Calcium oxytetracycline is typically formulated as a wettable powder and is most often 54 spray-applied on pear trees (and to a lesser extent, apple trees) at early bloom to help prevent fire blight 55 infection using ground or aircraft equipment (EPA 1988, 1993a, Guerena et al. 2003, PAN 2006a). 56 57 In addition to controlling fire blight, calcium oxytetracycline and/or oxytetracycline hydrochloride are 58 used to control pear decline, bacterial spot on peaches and nectarines, lethal yellowing of coconut palm, 59 and lethal decline of pritchardia palm (EPA 1993a). They are also used as an antifoulant when added to 60 marine paints to prevent the growth of barnacles. 61 62 Oxytetracycline was first isolated from soil containing the bacteria Streptomyces rimosus in 1948 and was the 63 second of the tetracycline antibiotics to be discovered (Hlavka et al. 1992, Klajn 2001). It and its many 64 derivatives (including calcium oxytetracycline) have been used extensively for over fifty years in medical 65 and veterinary practice and agriculturally as pesticides for over 30 years (EPA 1993a, HSDB 2003a). It is 66 also an important drug for use at public and private fish hatcheries, including facilities culturing 67 threatened and endangered fish (DEPA 2002, USGS 2003). Oxytetracycline, like other tetracyclines, is used 68 to treat bacterial infections, both common (e.g., respiratory tract, sinuses, middle ear, urinary tract) and rare 69 (e.g., anthrax, plague, cholera, Legionnaire’s disease) (Dale and Mandelstam 2005) As with other 70 tetracyclines, however, its use for treating these infections has become less common in the past decade due 71 to its reduced effectiveness from increased resistance to its antibiotic action among targeted pathogens. 72 73 Approved Legal Uses of the Substance: 74 Calcium oxytetracycline is a registered pesticide under the Federal Insecticide, Fungicide, and Rodenticide 75 Act (FIFRA), which is administered by the U.S. Environmental Protection Agency (EPA). EPA issued a 76 Registration Standard for oxytetracycline, oxytetracycline hydrochloride, and calcium oxytetracycline in 77 December 1988 (EPA 1988) and a reregistration eligibility decision (RED4) in March 1993 (EPA 1993a, 78 1993b). A TRED5 for oxytetracycline (i.e., calcium oxytetracycline and oxytetracycline hydrochloride) is

2 EPA has concluded that “the toxicity of all three oxytetracyclines [oxytetracycline, calcium oxtetracycline, oxytetracyline hydrochloride] is expected to be similar, and data generated on one compound can be used to assess exposure/risks of the other two” (EPA 1993a). 3 Fire blight is a widespread bacterial disease caused by Erwinia amylovora that can severely damage apples, pears, and other ornamental shrubs and trees. Affected branches and twigs wither and turn black or brownish-black, as if burned. Under the bark, bacteria form a canker where they can survive the winter and emerge to infect more trees the following year. Fire blight can be transmitted by bees, aphids, or other insects, and can spread by pruning (especially during the growing season) and blowing wind and rain. Boyd and Jacobi (2005), McManus and Heimann (1997), and Ritchie and Sutton (2002) provide further information about fire blight and options for its control. 4 When EPA completes the review and risk management decision for a pesticide that is subject to reregistration (i.e., one initially registered before November 1984), EPA generally issues a Reregistration Eligibility Decision or RED document. The RED document summarizes the risk assessment conclusions and outlines any risk reduction measures necessary for the pesticide to continue to be registered in the United States (see EPA 2005b for further information). 5 TRED documents are reports on FQPA (Food Quality Protection Act) Tolerance Reassessment Progress and (Interim) Risk Management Decisions (see EPA 2005b for further information). January 27, 2006 Page 2 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

79 scheduled for May 2006 (EPA 2005a). Tolerances (maximum legal residue levels) of 0.35 parts per million 80 (ppm) are established for residues of these oxytetracycline pesticides in or on raw peaches, nectarines, and 81 pears (40 CFR 180.337; EPA 1995). 82 83 Calcium oxytetracycline is regulated by the U.S. Food and Drug Administration (FDA) as an oral and 84 injectable prescription drug (FDA 1999) and is to be prescribed only by a physician (MedlinePlus 2001). 85 Veterinary and aquaculture use of oxytetracycline hydrochloride is also regulated by the FDA (CFR 21, 86 Chapter I, Part 520, §520.2158a). 87 88 Action of the Substance: 89 Tetracyclines, including calcium oxytetracycline, are characterized by their antimicrobial efficacy against a 90 wide range of Gram-positive and Gram-negative bacteria (Klajn 2001). They inhibit several processes 91 essential for the survival and growth of bacterial cells, most notably synthesis of bacterial proteins (Klajn 92 2001, Ophardt 2003). Tetracyclines also alter bacterial membranes and cause the leakage of genetic material 93 and other compounds out of the cells (Klajn 2001). 94 95 Status 96 97 International 98 Calcium oxytetracycline is not specifically listed for the petitioned use or other uses in the following 99 international organic standards: 100 101 • Canadian General Standards Board 102 • CODEX Alimentarius Commission 103 • Japan Agricultural Standard for Organic Production 104 105 The European Economic Community (EEC) Council Regulation 2092/91 prohibits the use of all antibiotics 106 in organic crop production; furthermore, U.S. organic crop producers that use antibiotics (including 107 calcium oxytetracycline) are not eligible to label and sell their products as “organic” within the European 108 Union. The use of antibiotics is also prohibited in crop production under the Basic Standards of the 109 International Federation of Organic Agriculture Movements (IFOAM). CCOF (2005) and WSDA (2005) 110 compare current U.S. NOP standards with EEC and IFOAM standards, including lists of prohibited 111 substances in organic crop production. 112 113 Evaluation Questions for Substances to be used in Organic Crop or Livestock Production 114 115 Evaluation Question #1: Is the petitioned substance formulated or manufactured by a chemical process? 116 (From 7 U.S.C. § 6502 (21)) 117 118 No specific information was available on the commercial manufacture of calcium oxytetracycline. The 119 parent compound, oxytetracycline, is produced in commercial quantities through a fermentation process in 120 which naturally occurring bacteria produce the substance; the manufacturer then uses chemical processes 121 to isolate and purify the substance (Hlavka et al. 1992). Presumably, a further chemical treatment would be 122 needed to form calcium oxytetracycline. Klajn (2001) provides a detailed discussion of the chemical 123 synthesis of several tetracyclines, including oxytetracycline; see also Evaluation Questions #2 and #3 124 below. 125 126 Evaluation Question #2: Is the petitioned substance formulated or manufactured by a process that 127 chemically changes the substance extracted from naturally occurring plant, animal, or mineral sources? 128 (From 7 U.S.C. § 6502 (21).) 129 130 As stated above, no specific information was available on the commercial manufacture of calcium 131 oxytetracycline. The parent compound, oxytetracycline is a naturally occurring substance and is produced 132 in commercial quantities through a fermentation process (Hlavka et al. 1992). Presumably, chemical January 27, 2006 Page 3 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

133 alteration of the parent compound would be required to yield calcium oxytetracycline. See Evaluation 134 Question #3 below for further detail. 135 136 Evaluation Question #3: Is the petitioned substance created by naturally occurring biological 137 processes? (From 7 U.S.C. § 6502 (21).) 138 139 The parent compound, oxytetracycline, is created by naturally occurring soil bacteria (Streptomyces species) 140 and is produced in commercial quantities through a fermentation process (Hlavka et al. 1992, HSDB 2003a, 141 Klajn 2001). However, the processes used to extract and purify the substance from the bacteria and growth 142 media are not naturally occurring. No specific information was available on the commercial manufacture 143 of calcium oxytetracycline from the parent compound oxytetracycline (see also Evaluation Questions #1 144 and #2). 145 146 Evaluation Question #4: Is there environmental contamination during the petitioned substance’s 147 manufacture, use, misuse, or disposal? (From 7 U.S.C. § 6518 (m) (3).) 148 149 No specific information was available on environmental contamination resulting from the manufacture of 150 calcium oxytetracycline or the parent compound oxytetracycline. However, the commercial fermentation 151 of antibiotics usually takes about two to seven days and may require the use of several chemicals, such as 152 solvents and antifoaming agents (Sengha 1993). In 1998, EPA revised its water effluent limitations 153 guidelines and standards for the pharmaceutical manufacturing industry to control water pollution 154 discharged from these facilities (EPA 1998). Based on information EPA collected from 244 facilities, 155 fermentation operations may use solvents to isolate the substance from the broth and other impurities. 156 Usually, the solvents are recovered and reused, but small amounts of the solvents may remain in the broth 157 “washes” that are discharged into the facility’s wastewater. The solvents most frequently used in 158 fermentation operations, according to the data collected, include acetone, methanol, isopropanol, ethanol, 159 amyl alcohol, and methyl isobutyl ketone. Specific information for the production of oxytetracycline was 160 not provided, so it is unclear whether manufacturers of calcium oxytetracycline actually use solvents. 161 Other pollutants that could be discharged from fermentation processes include detergents and 162 disinfectants used to clean equipment. Nitrogen and sulfur oxide gases may also be produced, which are 163 regulated by EPA. Assuming calcium oxytetracycline manufacturers comply with applicable water and air 164 regulations, it is unlikely that environmental contamination will result from fermenting processes. 165 166 The Pollution Prevention and Abatement Handbook: Pharmaceuticals Manufacturing (IFC 1998) includes a 167 general discussion of environmental pollution and opportunities to diminish pollution associated with the 168 manufacture of pharmaceuticals, including antibiotics such as calcium oxytetracycline. 169 170 EPA waived all environmental fate data requirements for calcium oxytetracycline pesticides due to their 171 limited pesticide use patterns and the availability of published literature that showed that oxytetracycline 172 pesticides are absorbed and inactivated in soils, especially soils with high clay content (EPA 1993a, 1993b). 173 EPA’s determination can be applied to fire blight control in organic crop production, as presently allowed 174 by the National List, which is a pesticidal use. Thus, for the specific proposed use (i.e., fire blight control), 175 it is unlikely that calcium oxytetracycline will contaminate the environment. 176 177 Furthermore, the labeling and safety information on pesticides that is provided to users is intended to help 178 prevent environmental contamination. Spilled calcium oxytetracycline materials should be swept up and 179 placed in a container for onsite disposal or at an approved waste disposal facility (Greenbook 2004a, 180 2004b). Contaminated surfaces should be scrubbed with hard water detergent and water. 181 182 Evaluation Question #5: Is the petitioned substance harmful to the environment? (From 7 U.S.C. § 6517 183 (c) (1) (A) (i) and 7 U.S.C. § 6517 (c) (2) (A) (i).) 184 185 EPA determined that “use of the active ingredients hydroxytetracycline monohydrochloride 186 [oxytetracycline hydrochloride] and oxytetracycline calcium in accordance with approved labeling will not 187 result in unreasonable adverse effects to…the environment” (EPA 1993a). EPA further noted that there are

January 27, 2006 Page 4 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

188 no environmental concerns associated with naturally-produced tetracycline. Thus, if used in accordance 189 with NOP regulations and labeled instructions, it is unlikely that calcium oxytetracycline or its breakdown 190 products will be harmful to non-target organisms or the environment (see also Evaluation Question #10 191 below). 192 193 Evaluation Question #6: Is there potential for the petitioned substance to cause detrimental chemical 194 interaction with other substances used in organic crop or livestock production? (From 7 U.S.C. § 6518 195 (m) (1).) 196 197 No published information was available to assess whether spray-applied calcium oxytetracycline or its 198 byproducts can cause detrimental chemical interaction with other substances used in organic crop 199 production. EPA (1993a) cited studies that indicate that oxytetracycline was absorbed and inactivated by 200 clays. Because there are no concerns with naturally-produced tetracycline (EPA 1993a), it seems unlikely 201 that calcium oxytetracycline, if used in accordance with NOP regulations and labeled instructions, would 202 cause detrimental chemical interaction with other substances used in organic farming. 203 204 Evaluation Question #7: Are there adverse biological or chemical interactions in the agro-ecosystem by 205 using the petitioned substance? (From 7 U.S.C. § 6518 (m) (5).) 206 207 No information was available to assess whether spray-applied calcium oxytetracycline or its byproducts 208 can have adverse biological or chemical reactions in the agro-ecosystem. As noted in Evaluation Question 209 #5, when properly labeled and used in accordance with labeled instructions (EPA 1993a, 1993b), calcium 210 oxytetracycline should not pose a significant risk to the environment. Therefore, it seems unlikely that 211 proper use of calcium oxytetracycline to control fire blight in organic crop production would cause any 212 adverse chemical or biological interactions in the agro-ecosystem. 213 214 Evaluation Question #8: Are there detrimental physiological effects on soil organisms, crops, or 215 livestock by using the petitioned substance? (From 7 U.S.C. § 6518 (m) (5).) 216 217 No information was available to assess whether spray-applied calcium oxytetracycline or its byproducts 218 can cause detrimental effects on soil organisms, crops, or livestock. However, the toxicity of veterinary 219 oxytetracycline to bacteria that has accumulated in the sediment of fish farms has been shown to decline 220 rapidly over time (DEPA 2002). Binding of the antibiotic to positively charged ions (e.g., magnesium) and 221 other substances in the sediment has been proposed as a possible explanation for the biological inactivation 222 of oxytetracycline. Furthermore, although calcium oxytetracycline has the potential to be toxic to 223 microorganisms in the soil, it is also produced by naturally occurring soil bacteria (EPA 1993a). 224 225 As noted previously (see Evaluation Question #5), EPA determined that use of calcium oxytetracycline in 226 accordance with approved labeling will not result in unreasonable adverse effects to the environment, 227 which includes the subsurface environment. 228 229 Evaluation Question #9: Is there a toxic or other adverse action of the petitioned substance or its 230 breakdown products? (From 7 U.S.C. § 6518 (m) (2).) 231 232 EPA (1993a) stated that the toxicity of all three oxytetracyclines is expected to be similar, and data 233 generated on one compound can be used to assess exposure/risks of the other two. 234 235 Based on acute toxicity studies in the published literature, calcium oxytetracycline is practically non-toxic 236 to birds, fish, aquatic invertebrates, and non-target insects such as honey bees (EPA 1993a, 1993b). 237 Therefore, EPA classified it as a Toxicity Category IV pesticide, indicating the lowest level of acute toxicity. 238 Several studies have been conducted using laboratory animals to determine the potential adverse effects of 239 oxytetracyclines in humans from their medicinal use and in other animals from veterinary use (EPA 1988, 240 1993a, HSDB 2003a, NTP 2006). For example, 14-day feeding studies of oxytetracycline hydrochloride in 241 mice and rats showed no adverse health effects (EPA 1993a). One developmental toxicity study with 242 oxytetracycline hydrochloride in rats showed a high incidence of maternal deaths and adverse health

January 27, 2006 Page 5 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

243 effects in offspring; however, extremely high dose levels were used. A similar experiment with mice 244 yielded no effects. Carcinogenicity studies showed no evidence of cancer in mice and some equivocal 245 evidence of cancer in male and female rats orally administered oxytetracycline hydrochloride in extremely 246 high doses. Oxytetracycline hydrochloride has been found to exhibit mostly negative results in a series of 247 tests designed to show whether chemicals interact with DNA or damage chromosomes, indicating it is 248 unlikely to cause cancer (NTP 2006). In this regard, EPA has classified calcium oxytetracycline as a “Group 249 D” carcinogen—one that is “not classifiable as to human carcinogenicity.” 250 251 Calcium oxytetracycline, related oxytetracyclines, and tetracyclines in general have been used as beneficial 252 human and animal drugs for several decades. MedlinePlus (2001) summaries side effects and 253 contraindications associated with the medical use of tetracyclines. Such adverse health effects commonly 254 include increased sensitivity of skin to sunlight and uncommonly include abdominal pain, headache, loss 255 of appetite, nausea and vomiting, and yellowing skin. In addition, medical use of oxytetracycline has 256 produced allergic reactions in some patients (EPA 1993a). 257 258 Evaluation Question #10: Is there undesirable persistence or concentration of the petitioned substance 259 or its breakdown products in the environment? (From 7 U.S.C. § 6518 (m) (2).) 260 261 Veterinary oxytetracycline has been found to have a half-life of 30 days in fresh water (pH = 7) but only 30 262 hours in sea water (pH = 8) (DEPA 2002). While abiotic degradation of antibiotics is the dominant 263 breakdown process in the water, microbial degradation appears to be the main breakdown pathway in 264 sediments. For example, the persistence of oxytetracycline in anoxic (no oxygen) bottom sediment deposits 265 of fish farms has been investigated and found to be relatively high (estimated half-life of approximately 10 266 weeks); degradation occurs much more slowly in deeper layers of the sediment compared to top layers. 267 Although the factors affecting the degradation of antibiotics in water and sediments are not completely 268 understood, temperature, water flow, bacterial activity, chemical composition, and depth of the sediment 269 will affect the decomposition and/or leaching of antibiotics, including oxytetracyclines. Oxytetracycline 270 pesticides are absorbed and inactivated in dry soils, especially those with high clay content (EPA 1993b). 271 272 Evaluation Question #11: Is there any harmful effect on human health by using the petitioned 273 substance? (From 7 U.S.C. § 6517 (c) (1) (A) (i), 7 U.S.C. § 6517 (c) (2) (A) (i)) and 7 U.S.C. § 6518 (m) (4).) 274 275 EPA (1993a) concluded that risks from dietary and occupational exposure to pesticides containing calcium 276 oxytetracycline are negligible and that chronic dietary risks posed by all food uses of oxytetracycline 277 pesticides are well below tolerance levels that would reasonably cause public health concern. 278 279 Workers (pesticide mixers, loaders, and applicators) are likely to be exposed to greater amounts of calcium 280 oxytetracycline than the general public during its application to pears, peaches, and nectarines using foliar 281 application methods6; fieldworkers also can be exposed post-application (EPA 1988). As stated above, EPA 282 (1993a) concluded that risks from such exposures are negligible. EPA further concluded that label 283 requirements will address concerns with potential allergic responses in oxytetracycline-sensitive people as 284 well as the potential development of microbial resistance to oxytetracyclines. For this reason, pesticides 285 containing calcium oxytetracycline registered for use on agricultural crops by foliar application methods 286 must include the following restricted entry after application and protective clothing statements on the label 287 (EPA 1993a): 288 289 ƒ Entry into treated orchards (or “areas”) is prohibited for 12 hours following application. 290 ƒ Prolonged or frequently repeated exposure may cause allergic reactions in some individuals. Do not 291 breathe dust or spray mist. Wear a MSHA/NIOSH approved TC-21C dust/mist filtering respirator, long 292 sleeved shirt, pants, shoes, and chemical-resistant gloves while handling or applying this product. Wash 293 thoroughly after handling or applying.

6 The process of spraying a liquid onto the leaves of plants, such as fruit trees using a spray gun attached to a tank. January 27, 2006 Page 6 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

294 Evaluation Question #12: Is there a wholly natural product which could be substituted for the 295 petitioned substance? (From 7 U.S.C. § 6517 (c) (1) (A) (ii).) 296 297 Using fire blight-resistant fruit trees (cultivars) can be considered an effective start to managing this plant 298 disease (Boyd and Jacobi 2005, Guerena et al. 2003, McManus and Heimann 1997). For example, there are 299 several strains of pears and apples with a comparatively high level of fire blight resistance that are adapted 300 to most of the contiguous United States. However, blight resistance for many of these cultivars appears to 301 vary with growing conditions and cultivation practices, and none are completely immune (see Evaluation 302 Question #14). 303 304 The use of biological control methods has long been an attractive goal for integrated crop management 305 programs and, in some cases, they have proven to be effective. There are several bacterial antagonists that 306 have shown good effectiveness in protecting against fire blight (Steiner 1998). For example, one such 307 material has been marketed since the mid-1990s as Blight Ban uses a strain (A506) of the bacterium, 308 Pseudomonas fluorescens (Guerena et al. 2003, Steiner 1998). This biological agent multiplies rapidly, 309 colonizes open flowers, and excludes any significant subsequent colonization by the fire blight 310 microorganism (Erwinia amylovora). However, tests have shown that this biological antagonist is not 311 effective if applied after Erwinia amylovora is already present; it is, however, about as effective as calcium 312 oxytetracycline (Stockwell et al. 2004). 313 314 Evaluation Question #13: Are there other already allowed substances that could be substituted for the 315 petitioned substance? (From 7 U.S.C. § 6518 (m) (6).) 316 317 Yes. NOP §205.601(i)(7) allows “Peracetic acid - for use to control fire blight bacteria” (USDA 2000) and 318 §205.601(i)(10) allows “Streptomycin [streptomycin and streptomycin sulfate], for fire blight control in 319 apples and pears only.” More broadly, §205.601(i) allows eight other synthetic substances and groups of 320 related substances for plant disease control in organic crop production. For example, “Bordeaux mix” 321 (copper sulfate and lime; both approved for use under §205.601(i)) has been used successfully to control 322 fire blight of pears and apples (Boyd et al. 2005, Steiner 1998). The effectiveness of copper against various 323 pathogens is attributed to the availability of copper ions that inactivate many different microorganism 324 enzymes and other proteins essential to cell membrane function. However, this broad mode of action is 325 not restricted to microorganisms and can also damage foliage and fruit on the crop plant, especially apples 326 (Steiner 1998). Indeed, the potential for phytotoxicity to apples is the single most important factor limiting 327 the effective use of Bordeaux mix and other copper-containing mixtures against fire blight. These and 328 other copper formulations, if sprayed at, or before green-tip stage (i.e., buds showing ¼” of green tissue), 329 provide some protection to apples and pears from fire blight infection (Guerena et al. 2003, McManus and 330 Heimann 1997). 331 332 Evaluation Question #14: Are there alternative practices that would make the use of the petitioned 333 substance unnecessary? (From 7 U.S.C. § 6518 (m) (6).) 334 335 Because fire blight development is greatly favored by the presence of young, succulent tissues, cultural 336 practices that favor moderate growth of trees are recommended (Boyd and Jacobi 2005, Guerena et al. 2003, 337 McManus and Heimann 1997). Such practices include use of drip irrigation and limiting or excluding the 338 use of fertilizers (including manure as currently allowed under NOP §205.203 (d)(5)), which can limit fast- 339 growing succulent tissue (McManus and Heimann 1997). The structure and mineral content of the soil are 340 important in managing fire blight because trees planted in poorly drained soil are more susceptible to fire 341 blight (Boyd and Jacobi 2005). In addition, careful pruning, disinfection of all tools used in pruning, 342 and/or pruning during the winter, when lower temperatures render the bacteria inactive, can help prevent 343 spreading the disease from infected to uninfected trees. 344 345 References 346 347 Boyd, J.E., Jacobi, W.R. 2005. Fire Blight. Report #2.907. Colorado State University Cooperative Extension. 348 http://www.ext.colostate.edu/pubs/Garden/02907.html.

January 27, 2006 Page 7 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

349 CCOF (California Certified Organic Growers International). 2005. CCOF's Draft Manual III: Global Market 350 Access Program. http://www.ccof.org/pdf/GlobalMarketAccessDraftForReview.pdf. 351 352 Dale, M.M., Mandelstam, J. 2005. Antiobiotics. Microsoft Encarta Online Encyclopedia. 353 http://encarta.msn.com/encnet/refpages/RefArtTextonly.aspx?refid=761577894&find=1. 354 355 Danish Environmental Protection Agency (DEPA). 2002. Environmental Assessment of 356 Veterinary Medicinal Products in Denmark. Environmental Project No. 659. 357 http://www.mst.dk/udgiv/publications/2002/87-7944-971-9/pdf/87-7944-972-7.pdf. 358 359 EPA (U.S. Environmental Protection Agency). 1988. Oxytetracycline EPA Pesticide Fact Sheet 12/88. 360 Available online at: http://pmep.cce.cornell.edu/profiles/fung-nemat/febuconazole- 361 sulfur/oxytetracycline/fung-prof-oxytetracycline.html. 362 363 EPA. 1993a. R.E.D. FACTS: Hydroxytetracycline Monohydrochloride and Oxytetracycline Calcium. EPA- 364 738-F-93-001. Office of Prevention, Pesticides And Toxic Substances. 365 http://www.epa.gov/oppsrrd1/REDs/factsheets/0655fact.pdf. 366 367 EPA. 1993b. Reregistration Eligibility Document (RED): Hydroxytetracycline Monohydrochloride 368 and Oxytetracycline Calcium. Office of Pesticides And Toxic Substances. 369 http://www.epa.gov/oppsrrd1/REDs/old_reds/hydroxytetracycline.pdf. 370 371 EPA. 1995. Potassium Oleate, Oxytetracycline, and S-Ethyl Diisobutylthiocarbamate; Tolerance Actions; 372 Final Rule. Federal Register 60(128): 34869-34871. 373 374 EPA 1998. Development Document for Final Effluent Limitations Guidelines and Standards for the 375 Pharmaceutical Manufacturing Point Source Category. EPA-821-R-98-005. Office of Water. 376 http://www.epa.gov/guide/pharm/techdev.html. 377 378 EPA. 2005a. Pesticide Reregistration Status. http://cfpub.epa.gov/oppref/rereg/status.cfm?show=rereg. 379 380 EPA 2005b. Definitions: REDs, IREDs, and TREDs. 381 http://www.epa.gov/oppsrrd1/reregistration/definitions.htm. 382 383 FDA (U.S. Food and Drug Adminstration). 1999. Prescription and Over-the-Counter Drug Product List - 384 19th Edition - Cumulative Supplement Number 5: May 1999. 385 http://www.fda.gov/cder/rxotcdpl/pdpl_0599.htm. 386 387 Greenbook 2004a. Material Data Safety Sheet: Mycoshield. 388 http://www.greenbook.net/docs/Msds/M76377.PDF. 389 390 Greenbook 2004b. Label: Mycoshield. http://www.greenbook.net/docs/Label/L76376.PDF. 391 392 Guerena, M., Born, H., Mumma, T. 2003. Organic Pear Production: Horticulture Production Guide. 393 ATTRA--National Sustainable Agriculture Information Service. http://attra.ncat.org/attra- 394 pub/pear.html#Diseases. 395 396 Hlavka, J.J. Ellestad, G.A., Chopra, I. 1992. Antibiotics (Tetracyclines). Kirth-Othmer Encyclopedia of 397 Chemical Technology, Volume 3 (Fourth Edition). New York: John Wiley & Sons. 398 399 HSDB (Hazardous Substances Data Bank). 2003a. Oxytetracycline. http://toxnet.nlm.nih.gov/. 400 401 HSDB (Hazardous Substances Data Bank). 2003b. Tetracycline. http://toxnet.nlm.nih.gov/. 402

January 27, 2006 Page 8 of 9 Technical Evaluation Report Tetracycline (Oxytetracycline Calcium Complex) Crops

403 IFC (International Finance Corporation). 1998. Pollution Prevention and Abatement Handbook: 404 Pharmaceuticals Manufacturing. 405 http://ifcln1.ifc.org/ifcext/enviro.nsf/AttachmentsByTitle/gui_pharmmfg_WB/$FILE/pharma_PPAH.p 406 df. 407 408 Klajn, R. 2001. Tetracycline: Chemistry and Chemical Biology of Tetracyclines. 409 http://www.chm.bris.ac.uk/motm/tetracycline/tetracycline.htm. 410 411 McManus, P.S., Heimann, O.S.F. 1997. Apple, Pear, and Related Tree Disorders: Fire Blight. Report A1616. 412 University of Wisconsin Cooperative Extension. http://cecommerce.uwex.edu/pdfs/A1616.PDF. 413 414 MedlinePlus. 2001. Drugs & Supplements: Tetracyclines (Systemic). 415 http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202552.html. 416 417 National Toxicology Program (NTP). 2006. NTP Studies on Oxytetracycline Hydrochloride. http://ntp- 418 apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.ntpstudiesforchemical&cas_no=2058-46-0. 419 420 Ophardt, C.E. 2003. Introduction to Drug Action: Other Antibiotics. 421 http://www.elmhurst.edu/~chm/vchembook/654antibiotic.html. 422 423 PAN (Pesticides Action Network). 2006a. PAN Pesticides Database - Pesticide Registration Status: Calcium 424 Oxytetracycline. http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id=PC36453, 425 426 PAN (Pesticides Action Network). 2006b. PAN Pesticides Database - Pesticide Registration Status: 427 Oxytetracycline. http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id=PC38140. 428 429 Ritchie, D.F., Sutton, T.B. 2002. Fire Blight of Apple and Pear. Fruit Disease Information Note 3. Plant 430 Pathology Extension. North Carolina State University. 431 http://www.ces.ncsu.edu/depts/pp/notes/oldnotes/fd3.htm. 432 433 Sengha, S. 1993. Fermentation. Kirth-Othmer Encyclopedia of Chemical Technology, Volume 10 (Fourth 434 Edition). New York: John Wiley & Sons. 435 436 Steiner, P.W. 1998. How Good Are Our Options with Copper, Bio-controls and Alliette for Fire Blight 437 Control? West Virginia University, Kearneysville Tree Fruit Research and Education Center. 438 http://www.caf.wvu.edu/kearneysville/articles/SteinerHort2.html. 439 440 Stockwell, V.O., Temple, T.N., Johnson, K.B., Loper, J.E. 2004. Effect of the Iron Chelate FeEEDHA on 441 Control of Fire Blight by Pseudomonas Fluorescens A506. 10th International Workshop on Fire Blight. 442 http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=160229. 443 444 USDA (U.S. Department of Agriculture,). 2000. TAP Review: Peracetic Acid. USDA National Organic 445 Program. http://www.ams.usda.gov/nop/NationalList/TAPReviews/PeraceticAcid.pdf. 446 447 USGS (U.S. Geological Survey). 2003. Expansion of Oxytetracycline in Immersion and Feed Additive for 448 Control of Bacterial Diseases and Otolith Marking on Cultured Freshwater Fish. USGS Upper Midwest 449 Environmental Sciences Center. 450 http://www.umesc.usgs.gov/aquatic/drug_research/gstehly_5002553.html. 451 452 WSDA (Washington State Department of Agriculture). 2005. Organic Food: European Organic Verification 453 Program (EOVP). http://agr.wa.gov/FoodAnimal/Organic/default.htm. 454

January 27, 2006 Page 9 of 9